Background. Solid organ transplanted patients have a three-to fourfold higher lifetime risk of developing a cancer than the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.6ϫ10,000 PY), and 22 of them developed a SPC (annual incidence: 3.9ϫ10,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.8ϫ10,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83-1.41). Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy

Diego Serraino

Domenico Montanaro

Eloisa Arbustini

Emanuela Taioli

Luigi Boschiero

Mario Scalamogna

Paola Pedotti

Patrizia Burra

Pierluca Piselli

Silvio Sandrini

CiteSeerX

RAPID COMMUNICATION
Incidence of Second Primary Cancer in Transplanted
Patients
Emanuela Taioli,1,19 Pierluca Piselli,2 Eloisa Arbustini,3 Luigi Boschiero,4 Patrizia Burra,5 Ghil Busnach,6
Rossana Caldara,7 Franco Citterio,8 Emanuela De Juli,9 Daniela Dissegna,10 Eliana Gotti,11
Francesco Marchini,12 Maria Cristina Maresca,13 Luigina Marsano,14 Giuseppe Montagnino,15
Domenico Montanaro,16 Silvio Sandrini,17 Paola Pedotti,18 Mario Scalamogna,18 and Diego Serraino2
Background. Solid organ transplanted patients have a three- to fourfold higher lifetime risk of developing a cancer than
the general population. However, the incidence of a second primary cancer in transplanted patients has never been
studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them
a very attractive model.
Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney,
liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years.
Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.610,000 PY), and 22 of
them developed a SPC (annual incidence: 3.910,000 PY). The annual incidence of a SPC in the transplanted patients
who developed a first cancer was 107.810,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83–1.41).
Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study
does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.
Keywords: Epidemiology, Cohort study, Solid organ transplant.
(Transplantation 2006;81: 982–985)
The increasing access to sophisticated tools for early detec-tion of cancer and the improving therapeutic schemes
have modified the natural history of several types of cancer,
and have largely increased the population size of cancer sur-
vivors. These subjects are exposed to the possibility of recur-
rence, or to the development of a second primary cancer
(SPC) (1– 4); this is a cancer that based on time of occurrence,
histological type, and site could be defined as a new event,
rather than a metastasis or a recurrence of the first neoplasm.
The risk of developing a SPC could be related to the persis-
tence of environmental risk factors associated with the first
cancer, and this is particularly evident for tobacco-related
cancers (5–10). Individual susceptibility to carcinogens as
well as other genetic factors could be responsible for the de-
velopment of a SPC (11–13). Furthermore, cancer patient
survivors undergo more frequent and accurate screening pro-
grams and diagnostic scrutiny than non cancer patients, thus
increasing the possibility of a detection bias.
Solid organ transplanted patients have a three- to four-
fold higher lifetime risk of developing a cancer than the gen-
eral population, with several hundred fold higher risks for
certain types of virus related cancers, such as Kaposi’s sar-
coma (KS) and posttransplant lymphoproliferative diseases
(PTLD) (14 –16). At the best of our knowledge, the incidence
This study was partially supported by a grant from the Italian Ministry of
Health (COBM/F 1).
1 University of Pittsburgh Cancer Institute, Pittsburgh, PA.
2 Dipartimento di Epidemiologia, Istituto Nazionale per le Malattie Infettive
Lazzaro Spallanzani, IRCCS, Rome, Italy.
3 Laboratorio di Diagnostica Molecolare, Patologia Cardiovascolare e dei
Trapianti, Policlinico S. Matteo, IRCCS, Pavia, Italy.
4 A.O. di Verona, Verona, Italy.
5 Sezione di Gastroenterologia, Dipartimento di Scienze Chirurgiche e Gas-
troenterologiche, Universita’ di Padova, Italy.
6 Unità Nefrologia, Dialisi & Terapia Trapianto Renale, Osp Niguarda Ca’
Granda, Milan, Italy.
7 IRCCS San Raffaele, Milan, Italy.
8 Clinica Chirurgica, Univ Cattolica Sacro Cuore, Policinico “A. Gemelli,”
Rome, Italy.
9 Divisione di Pneumologia, Osp Niguarda Ca’ Granda, Milan, Italy.
10 A.O. San Bortolo, Vicenza, Italy.
11 A.O. Ospedali Riuniti, Bergamo, Italy.
12 A.O. di Padova, Padova, Italy.
13 A.O. Ca’ Foncello, Treviso, Italy.
14 A.O. San Martino, Genova, Italy.
15 Nephrology Department, IRCCS Fondazione Policlinico, Milan, Italy.
16 Dipartimento Interaziendale di Trapianto d’Organo e di Tessuti, Udine, Italy.
17 A.O. Spedali Civili, Brescia, Italy.
18 Servizio per il Prelievo e la Conservazione di Organi e Tessuti. IRCCS,
Ospedale Maggiore Policlinico, Milan, Italy.
19 Address correspondence to: Emanuela Taioli, M.D., Ph.D., University of
Pittsburgh Cancer Institute, 5150 Centre Ave., Pittsburgh, PA 15232.
E-mail: taiolien@upmc.edu
Received 4 November 2005. Revision requested 2 December 2005.
Accepted 22 December 2005.
Copyright © 2006 by Lippincott Williams & Wilkins
ISSN 0041-1337/06/8107-982
DOI: 10.1097/01.tp.0000203321.42121.14
982 Transplantation • Volume 81, Number 7, April 15, 2006
of a SPC in transplanted patients has never been studied, de-
spite the fact that the presence of regular follow-ups and the
increased survival of these patients make them a very attrac-
tive model.
The aim of the present study was to investigate the in-
cidence of a SPC in a network of Italian cohorts of kidney,
liver, lung, and heart transplanted patients.
MATERIALS AND METHODS
The study represents the combination of a cohort col-
lected through the North Italian Transplant program (NITp),
and a network of cohorts collected through the Spallanzani
Institute.
The design of the NITp cohort has been described else-
where (14). Briefly, all the subjects who underwent a kidney
transplant from 1990 to 2004 in 10 transplant centers in-
cluded in the NITp area (San Raffaele and Policlinico, Milan;
San Martino, Genoa; Verona; Padova; Ca’ Foncello, Treviso;
Santa Maria della Misericordia, Udine; Ospedali Riuniti, Ber-
gamo; Spedali Civili, Brescia; San Bortolo, Vicenza) were re-
cruited.
The second network of cohorts includes anonymous
information on 2,755 transplants performed in five trans-
plant centers in Northern or Central Italy, 1,340 of which are
kidney transplants performed in the period 1972-2003 at Ni-
guarda Hospital, Milan, 504 kidney transplants performed
between 1970 and 2000 at Policlinico Gemelli Hospital,
Rome; 702 cardiac transplants performed between 1985 and
2004 at Policlinico S. Matteo, Pavia; 159 liver transplants per-
formed between 1990 and 2000 at Azienda Ospedale Univer-
sità, Padua; and 50 lung transplants performed between 1991
and 2000 at Niguarda Hospital, Milan.
All patients have signed an informed consent, which
included the possibility to be contacted for follow up infor-
mation. Along with an annual, active follow-up for each
transplanted subject, the centers were asked to register all
newly diagnosed cancers, identified either during their pro-
grammed usual clinical follow-up, or through telephone con-
tact of the patients or their family members. This strategy of
active surveillance has been put in place in order to avoid
underreporting of cases. Data were entered in an electronic
data base furnished by our Institute, which included personal
information (age at transplant, sex, blood group, anti-HLA
antibodies), transplant’s information (date, transplant cen-
ter, donor data, HLA mismatch, cold ischemic time, length of
follow-up) and cancer data (site, type, date of diagnosis). Pa-
tients who survived less than 10 days after transplant, patients
with a pretransplant history of any cancer, and patients who
developed cancer within 30 days from transplant were ex-
cluded from this study, according to the protocol applied at
the time of the cohort’s recruitment (16). Both basal cell and
squamous carcinomas of the skin were excluded from the
data base because of possible underreporting; however, they
were included if they appeared as a SPC, since underreporting
of a second cancer in subjects who already suffered a first
malignancy is an unlikely event. A secondary analysis was
performed including skin squamous cell carcinoma in the
calculation of the incidence of both first and second primary
cancer.
A cancer diagnosed in a subject who already suffered a
malignancy after transplant, but was located in a different site
from the first cancer and was histologically defined by the
physician in charge of the patient as a “nonmetastatic” can-
cer, was recorded in this study as a SPC.
Each patient included in the cohort was actively fol-
lowed up from the date of transplant to the date of cancer
development, or death, and from the date of cancer develop-
ment to the date of SPC development or death or study end
date, for a total of 51,819 person-years (PY). First and second
cancer incidence rates were calculated as the observed num-
ber of cases divided by PY at risk in the whole cohort, and
according to gender and type of transplant. Standardized In-
cidence Ratio was calculated as the ratio between the inci-
dence of SPC in subjects who had a first cancer divided by the
incidence of the first cancer. 95% Confidence Intervals (CI)
were calculated assuming a Poisson distribution.
RESULTS
The whole cohort included 7,636 transplanted patients,
6,725 of which were kidney, 159 were liver, 702 were heart,
and 50 were lung transplants. During the follow-up period,
499 subjects were diagnosed with cancer, for an overall an-
nual incidence of 98.610,000 PY (95% CI: 90.0 –107.2). Dif-
ferences in cancer incidence rate were observed according to
gender: the incidence was 105.210,000 PY in males vs.
77.510,000 PY in females. Among the 7,636 patients in-
cluded in this analysis, 22 (0.3%) developed a SPC, with an
overall annual incidence of 3.910,000 PY (95% CI 2.2–5.6)
(Table 1). When the analysis was restricted to transplanted
patients who developed a first cancer, the incidence rate of a
SPC was 107.810,000 PY (95% CI 63.0 –152.6), yielding a
SIR1.1 (95% CI: 0.83–1.41).
TABLE 1. Incidence of second primary cancer in transplanted patients and patients who developed a first malignancy
after the transplant
N
Overall incidence of SPC
Incidence in patients with a
first cancer after transplant
Person-years
Incidence rate10,000
person-years (95% CI) Person-years
Incidence rate 10,000
person-years (95% CI)
Total 22 51,819 3.9 (2.2–5.6) 2,041 107.8 (63.0–152.6)
Sex Male 18 34,987 4.6 (2.3–6.8) 1,503 119.8 (64.8–174.8)a
Female 4 16,833 2.4 (0.1–4.7) 538 74.4 (1.8–147.1)b
a Standardized incidence ratio1.1.
b Standardized incidence ratio1.0.
© 2006 Lippincott Williams & Wilkins 983Taioli et al.
When squamous cell carcinoma of the skin was in-
cluded in the analysis, the incidence of first cancer was 117.7
10,000 PY, while the incidence of SPC in transplanted pa-
tients who developed a first cancer was 107.5, yielding a SIR of
0.97.
The details on the first and second cancers in subjects
who developed a SPC are reported in Table 2. Among solid
tumors, the most frequent combination was kidney followed
by skin cancer (n3), while among lymphoproliferative dis-
eases, two cases of Non Hodgkin Lymphoma (NHL) were
followed by KS and kidney cancer; 1 case of Hodgkin Lym-
phoma (HL) was followed by NHL. Among SPC sites, skin
cancer was the most frequent (n11), followed by liver, and
kidney (2 cases each).
The time of occurrence of the first tumor ranged from
33 to 5,585 days (mean 1,9431,648 days), while the time of
occurrence of the SPC after the first cancer ranged from 0 to
3,591 days (mean 778963 days).
DISCUSSION
We report for the first time the incidence rates of a SPC
in a network of cohorts of transplanted patients. Previous
work on SPC has focused on samples of cancer patients, in
order to analyze the carcinogenic mechanisms behind the de-
velopment of both the first and the second cancer. For exam-
ple, smoking related SPC in subjects affected by smoking re-
lated cancers (1, 5–10), and SPC of the reproductive organs in
subjects with reproductive related cancers have been de-
scribed (3, 11), as well as skin cancer following melanoma (4).
Among the 7,636 patients included in the present co-
hort, 0.3% of the subjects developed a SPC; when considering
only the transplanted individuals who developed a first can-
cer (n499) 4.0% of them were diagnosed with a SPC. This
figure is comparable to what has been previously published,
where the percentage of SPC ranges from 1 to 5% (1, 2, 5, 6,
17). However, such previous studies were restricted to sub-
jects with a specific type of first cancer, while the present study
has a cohort design, thus allowing calculation of the overall
incidence of a SPC. As far as the type of SPC is concerned, the
small number of second primary cases does not allow detect-
ing any specific pattern of occurrence. Although the inclusion
of squamous skin cancer may be questionable because of the
specific nature of this cancer, we have decided to include it in
order to give a global picture of SPC incidence in this popu-
lation. In order to reach a large enough population to study
patterns of occurrence of SPC, pooled analyses of trans-
planted patient registries would be necessary. This effort
would also allow the study of SPC in relation to type of solid
organ transplant and type of therapeutic regimen. In fact, a
limitation of our study is that the small number of second
primaries, along with the fact that immunosuppressive pro-
tocols have changed in Italy during the large time frame in
which the study was conducted, did not allow the analysis of
the association between drug type and dosage and SPC inci-
dence.
The incidence of cancer in transplanted patients is
known to be higher than in the general population, due to
immunosuppressive treatments and possible viral infections.
In the cohort described here, the overall annual incidence of
first cancer was 98.610,000 PY, corresponding to an in-
creased risk of nearly 2.3 fold compared to that in the general
population of the same sex and age (www.registri-tumori.it/
incidenza/main.htm). This result is in agreement with previ-
ously published data (14 –16). However, the incidence of
TABLE 2. Description of the subjects who developed a SPC
Subject
number
Type of
transplant
Type of
first cancer Type of SPC
Time between
transplant—
first cancer (days)
Time between
first cancer—
SPC (days)
1 Kidney Cervix Breast 2912 931
2 Kidney Gastric Liver 5585 0
3 Kidney Larynx Lung 4638 2215
4 Heart NHL Kidney 4130 1270
5 Kidney Kaposi’s Sarcoma Nasal mucosa 571 2761
6 Heart Bladder Skin—basal cell carcinoma 3892 0
7 Kidney Kidney Skin—squamous 4179 50
8 Kidney Melanoma Anus 502 3591
9 Liver Kaposi’s Sarcoma Liver 1167 1077
10 Kidney Burkitt lymphoma Skin—squamous 2698 20
11 Kidney Kidney Skin—basal cell carcinoma 1937 309
12 Kidney Kaposi’s Sarcoma Skin—squamous 313 440
13 Kidney Kidney Skin—basal cell carcinoma 1175 1180
14 Kidney Breast Skin—squamous 2416 960
15 Heart Colon Skin—basal cell carcinoma 174 406
16 Kidney Rectum Skin—squamous 2038 524
17 Kidney Hodgkin Lymphoma NHL 1405 713
18 Kidney Kaposi’s Sarcoma Skin—squamous 308 171
19 Kidney NHL Kaposi’s Sarcoma 1214 0
20 Kidney Kaposi’s Sarcoma Kidney 1297 14
29 Kidney Prostate Skin—squamous 33 185
22 Kidney Colon Melanoma 312 298
NHL, non-Hodgkin lymphoma.
984 Transplantation • Volume 81, Number 7, April 15, 2006
SPC in the subjects who developed a first cancer was
107.810,000 PY, suggesting an incidence comparable to the
incidence of the first cancer in the same population (Stan-
dardized Incidence Ratio1.1). This result suggests that
transplanted subjects who developed a first cancer do not
have a significantly higher risk of developing a second cancer
compared to their baseline risk of developing the first cancer,
at least in our sample.
In conclusion, our study does not indicate a significant
increased risk of SPC in transplanted subjects who already
suffered of a first malignancy. Therefore, the clinical indica-
tion deriving from this study is that regular screening proce-
dures should be applied to transplanted patients who had
cancer, while no special indication to more frequent screen-
ings or screening of specific sites in patients who already suf-
fered a first cancer is suggested by this study.
REFERENCES
1. Duchateau CSJ, Stokkel MPM. Second primary tumors involving non-
small cell lung cancer. Prevalence and its influence on survival. Clinc
Invest 2005; 127: 1152.
2. Aydiner A, Karadeniz A, Uygun K, et al. Multiple primary neoplasms at
a single Institution. Am J Clin Oncol 2000; 23: 364.
3. Bernstein JL, Lapinki RH, Thakore SS, et al. The descriptive epidemi-
ology of second primary breast cancer. Epidemiology 2003; 14: 552.
4. Crocetti E, Carli P. Risk of second primary cancer, other than mela-
noma, in an Italian population - based cohort of cutaneous malignant
melanoma patients. Europ J Cancer Prev 2004; 13: 33.
5. Teppo L, Slminen E, Pukkala E. Risk of a new primary cancer among
patients with lung cancer of different histological types. Europ J Cancer
2001; 37: 613.
6. Levi F, Randimbison L, Te VC, La Vecchia C. Second primary cancers
in patients with lung carcinoma. Cancer 1999; 86: 186.
7. Bhattacharyya N, Nayak VK. Survival outcomes for second primary
head and neck cancer: a matched analysis. Otolaryn Head Neck Surg
2005; 132: 63.
8. Franco EL, Kowalski IP, Kanda JL. Risk factors for second cancers of the
upper respiratory and digestive systems: a case control study. J Clin
Epidemiol 1991; 11: 615.
9. Day GL, Blot WJ, Shore RE, et al. Second cancers following oral and
pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst
1994; 86: 137.
10. Barbone F, Franceschi S, Talamini R, et al. A follow-up study of deter-
minants of second tumor and metastasis among subjects with cancer of
the oral cavity, pharynx, and larynx. J Clin Epidemiol 1996; 49: 367.
11. Chen Y, Thompson W, Semenciw R, Mao Y. Epidemiology of con-
tralateral breast cancer. Cancer Epidemiol Biomarkers Prev 1999; 8: 855.
12. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in fam-
ilies with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90: 606.
13. Li FP, Abramson DH, Tarone RE, et al. Hereditary retinoblastoma,
lipoma, and second primary cancers. J Natl Cancer Inst 1997; 89: 83.
14. Pedotti P, Cardillo M, Rossini G, et al. Incidence of cancer after kidney
transplant: results from the North Italy transplant program. Transplan-
tation 2003; 76: 1448.
15. Penn I. Tumors after renal and cardiac transplantation. Hem/Oncol
Clin North Am 1993; 7: 431.
16. Serraino D, Piselli P, Angeletti C, et al. Risk of Kaposi’s sarcoma and of
other cancers in Italian renal transplant patients. Br J Cancer 2005; 92:
572.
17. Kaneko S, Yamaguchi N. Epidemiological analysis of site relationships
of synchronous and metachronous multiple primary cancers in the Na-
tional Cancer Center, Japan, 1962–1996. Jpn J Clin Oncol 1999; 29: 96.
© 2006 Lippincott Williams & Wilkins 985Taioli et al.


Incidence of Second Primary Cancer in Transplanted Patients

http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=807A9E718535D60B3E0220A3566A937F?doi=10.1.1.1045.9451&rep=rep1&type=pdf

Incidence of Second Primary Cancer in Transplanted Patients

Abstract

Similar works

Full text

Available Versions

CiteSeerX